B01 VENETOCLAX TARGETED THERAPY in AL AMYLOIDOSIS PATIENTS: A RETROSPECTIVE ANALYSIS FROM THE FRENCH AMYLOIDOSIS NETWORK
Authors: M. Roussel, M. Pirotte, R. Gounot, K. Queru, O. Rizzo, B. Royer, S. Harel, E. Desport, A. Huart, M. Niault, L. Karlin, O. Decaux, T. Chalopin, B. Carpentier, M. Macro, M. Vignon, E. Chalayer, AM. Stoppa, F. Bridoux, A. Jaccard
Journal: HemaSphere (2023)

Background: BCL-2 inhibition represents a promising therapeutic approach in multiple myeloma (MM). Venetoclax (VEN) is an oral BCL-2-selective BH3 mimetic and is currently approved in CLL. VEN has shown activity in MM cell lines with t(11;14), in part because there may be greater BCL-2 co-dependence in such clones. VEN is safe in MM patients (pts) with encouraging clinical activity. VEN should provide a novel targeted therapy in AL amyloidosis as most of the pts harbored a t(11;14). Various retrospective cohorts are now reported with VEN alone or in combination with bortezomib (BOR) and/or daratumumab (DARA), with rapid and deep hem. responses. We report here on efficacy of VEN based regimen in AL amyloidosis pts in a real-life setting. Patients: This retrospective study included 51 pts with AL amyloidosis, from the French Amyloidosis Network, who received at least one cycle of VEN as part of their regimen. Individual data were prospectively and retrospectively collected. Responses were reviewed using current criteria for CR (serum/urine negative immunofixation and normal involved FLC) and for VGPR (differential FLC<40 mg/l). Median age was 62 years (54-70); 34 pts had >=2 organs involved with heart in 70.5% and kidney in 57.0%, MAYO stage 3/4 in 25 pts and median NT-proBNP and troponin levels of 1706 ng/l (IQR: 339-4275), 59 pg/ml (19-88), respectively. Median dFLC was 314 mg/l (IQR:133-565) and 32 pts had a dFLC>180 at diagnosis. Of note, 72.5% of pts were FLC only. Median plasma cells infiltration was 8% (IQR: 5-14). All except 3 pts had a t(11;14). Results: Median time from diagnosis to VEN therapy was 24 months (IQR:9-60). VEN (100-800 mg/day) was given alone (n=25), or with dexamethasone/DEXA (n=5), BOR (n=12), DARA (n=3), or all (n=6). Twelve pts received frontline VEN to deepen or restore response, and 39 received VEN at relapse with a median of 2 prior lines of therapy (min/max: 1–6); 37 pts were DARA exposed and 7 were DARA "refractory". Overall, 45% of pts never achieved >=VGPR with their previous line of therapy. Median dFLC was 74 (IQR: 45-133) at time of VEN. Median time on therapy was 9 mos (IQR:6-14): 34 pts discontinued VEN because of CR/VGPR (n=21), disease progression (n=7), toxicities (n=8) and/or death (n=6). The hematologic response rate was 90% with 61% CR, 14% VGPR, and 10% PR, 3 pts are not evaluable. Only 1/3 pt with no t(11;14) achieved CR. Responses were fast and median time to best response was 2.75 mos (IQR:1.05-3.00). Median DOR is 12.7 mos (IQR:7.0-18.9). For VEN monotherapy, 72% achieved >=VGPR and 56% CR; with the addition of DEX, BOR, DARA or both, CR was 60, and 67%, respectively for the last 3. In frontline pts, all except 3 achieved CR with the addition of VEN. In relapsed pts, 56.5% achieved CR and 18% VGPR. Considering DARA exposed/relapsed pts, 14/25 (56%) achieved CR, and 4 (16%) VGPR; considering the 7 R/R pts, 71% reached CR. With median FU of 17.2 mos, median PFS is 40 mos, and estimated 3-year OS 68.2% (SD 10.3); 10 pts died. VEN was well tolerated with no unexpected adverse events (AEs). Eighteen pts reported AEs, mainly diarrhea/nausea, neutropenia, infections and fatigue. Conclusion: Venetoclax in AL amyloidosis is a promising targeted therapy. With CR of >55% with VEN alone or VEN-based regimen, these results confirm the efficacy of VEN in pts with t(11;14) AL and support randomized clinical trials, even in daratumumab and/or bortezomib-exposed pts (and somehow refractory).